Tumor necrosis factor alpha (TNFα), a mononuclear cytokine, is predominately produced by monocytes and macrophages. It possesses various biological activities: (1) killing cancer cells or inhibiting growth of cancer cells, (2) enhancing the phagocytosis of neutrophilic granulocytes, (3) up-regulating the production of peroxide, and (4) killing infection pathogens.
TNFα is a potential target for treating disorders related to the expression of TNFα. These disorders include, but are not limited to, rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, spondyloarthropathies, inflammatory bowel disease (including Crohn's disease and ulcerative colitis), chronic heart failure, diabetes mellitus, systemic lupus erythematosus, scleroderma, sarcoidosis, polymyositis/dermatomyositis, psoriasis, multiple myeloma, myelodysplastic syndrome, acute myelogenous leukemia, Parkinson's disease, AIDS dementia complex, Alzheimer's disease, depression, sepsis, pyoderma gangrenosum, hematosepsis, septic shock, Behcet's syndrome, graft-versus-host disease, uveitis, Wegener's granulomatosis, Sjogren's syndrome, chronic obstructive pulmonary disease, asthma, acute pancreatitis, periodontal disease, cachexia, cancer, central nervous system injury, viral respiratory disease, and obesity (Ogata H, Hibi T. et al Curr Pharm Des. 2003; 9(14): 1107-13; Moller D R. et al J Intern Med. 2003 January; 253(1): 31-40; Taylor P C. Et al Curr Pharm Des. 2003; 9(14): 1095-106; Wilkinson N et al Arch Dis Child. 2003 March; 88(3): 186-91; Nishimura F et al J Periodontol. 2003 January; 74(1): 97-102; Weinberg J M et al Cutis. 2003 January; 71(1): 41-5; Burnham E et al Crit Care Med. 2001 March; 29(3): 690-1; Sack M. et al Pharmacol Ther. 2002 April-May; 94(1-2): 123-35; Barnes P J. Et al Annu Rev Pharmacol Toxicol. 2002; 42:81-98; Mageed R A et al Lupus. 2002; 11(12): 850-5; Tsimberidou A M et al Expert Rev Anticancer Ther. 2002 June; 2(3): 277-86; Muller T. et al Curr Opin Investig Drugs. 2002 December; 3(12): 1763-7; Calandra T et al Curr Clin Top Infect Dis. 2002; 22:1-23; Girolomoni G et al Curr Opin Investig Drugs. 2002 November; 3(11): 1590-5; Tutuncu Z et al Clin Exp Rheumatol. 2002 November-December; 20(6 Suppl 28): S146-51; Braun J et al Best Pract Res Clin Rheumatol. 2002 September; 16(4): 631-51; Barnes P J. Et al Novartis Found Symp. 2001; 234:255-67; discussion 267-72; Brady M, et al Baillieres Best Pract Res Clin Gastroenterol. 1999 July; 13(2): 265-89; Goldring M B. et al Expert Opin Biol Ther. 2001 September; 1(5): 817-29; Mariette X. Rev Prat. 2003 Mar. 1; 53(5): 507-11; Sharma R et al Int J Cardiol. 2002 September; 85(1): 161-71; Wang C X et al Prog Neurobiol. 2002 June; 67(2): 161-72; Van Reeth K et al Vet Immunol Immunopathol. 2002 Sep. 10; 87(3-4): 161-8; Leonard B E et al Int J Dev Neurosci. 2001 June; 19(3): 305-12; Hays S J et al Curr Pharm Des. 1998 August; 4(4): 335-48.).
Interleukin-1 beta (IL-1β), a cytokine secreted by cells such as monocyte macrophages and dendritic cells, mediates a wide range of immune and inflammatory responses. Modulating the expression of IL-1β leads to treatment of a variety of disorders, such as rheumatoid arthritis, hematosepsis, periodontal disease, chronic heart failure, polymyositis/dermatomyositis, acute pancreatitis, chronic obstructive pulmonary disease, Alzheimer's disease, osteoarthritis, bacterial infections, multiple myeloma, myelodysplastic syndrome, uveitis, central nervous system injury, viral respiratory disease, asthma, depression, and scleroderma (Taylor P C. et al Curr Pharm Des. 2003; 9(14): 1095-106; Dellinger R P et al Clin Infect Dis. 2003 May 15; 36(10): 1259-65; Takashiba S et al J Periodontol. 2003 January; 74(1): 103-10; Diwan A, et al Curr Mol Med. 2003 March; 3(2): 161-82; Lundberg I E, et al Rheum Dis Clin North Am. 2002 November; 28(4): 799-822; Makhija R, et al J Hepatobiliary Pancreat Surg. 2002; 9(4): 401-10; Chung K F. Et al Eur Respir J Suppl. 2001 December; 34:50s-59s; Hallegua D S, et al Ann Rheum Dis. 2002 November; 61(11): 960-7; Goldring M B. Et al Expert Opin Biol Ther. 2001 September; 1(5): 817-29; Mrak R E, Griffin W S. Et al Neurobiol Aging. 2001 November-December; 22(6): 903-8; Brady M, et al Baillieres Best Pract Res Clin Gastroenterol. 1999 July; 13(2): 265-89; Van der Meer J W, et al Ann N Y Acad Sci. 1998 Sep. 29; 856:243-51; Rameshwar P et al Acta Haematol. 2003; 109(1): 1-10; de Kozak Y et al Int Rev Immunol. 2002 March-June; 21(2-3): 231-53; Wang C X et al Prog Neurobiol. 2002 June; 67(2): 161-72; Van Reeth K et al Vet Immunol Immunopathol. 2002 Sep. 10; 87(3-4): 161-8; Stirling R G et al Br Med Bull. 2000; 56(4): 1037-53; Leonard B E et al Int J Dev Neurosci. 2001 June; 19(3): 305-12; Allan S M et al Ann N Y Acad Sci. 2000; 917:84-93; and Cafagna D et al Minerva Med. 1998 May; 89(5): 153-61).